The Olive Baboon model of Zika Virus induced fetal brain injury

寨卡病毒诱发胎儿脑损伤的橄榄狒狒模型

• 批准号: 9413669
• 负责人: DEAN MYERS
• 金额: $ 22.2万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9413669
• 关键词: Acute; Address; Aedes; Americas; Apoptosis; Area; Autophagocytosis; Autopsy; Behavioral; Biometry; Blood Vessels; Blood flow; Brain; Brain Pathology; Brain Stem; Brazil; Calcified; Cell Cycle Progression; Cell Differentiation process; Cells; Central Nervous System Diseases; Central Nervous System Infections; Cerebellar malformation; Cerebral cortex; Cerebrum; Clinical; Cognitive; Communities; Complement; Congenital Abnormality; Culicidae; Data; Development; Disease Outbreaks; Embryo; Epidemic; Experimental Animal Model; Fetal Death; Fetal Growth; Fetal Growth Retardation; Fetal Tissues; Fetus; First Pregnancy Trimester; Flavivirus; French Polynesia; Genetic; Gestational Age; Gliosis; Goals; Human; Immune; Immunology; Impairment; In Vitro; Infant; Infection; Infiltration; Inflammation; Inflammatory Response; Injury; International; Lead; Lesion; Link; Macaca nemestrina; Microcephaly; Mitotic; Modeling; Mus; Necrosis; Neurobiology; Neuroglia; Neurologic; Neurons; Oklahoma; Oligodendroglia; Oligohydramnios; Outcome; Oxidative Stress; Papio; Papio anubis; Pathologic; Pathology; Penetration; Phenotype; Physiology; Placenta; Placentation; Pregnancy; Primates; Proliferating; Radial; Reporting; Research; Resource Sharing; Resources; Rodent; Role; Second Pregnancy Trimester; Severities; Source; Structure; Study models; Telencephalon; Third Pregnancy Trimester; Time; Translations; Ultrasonography; Umbilical Blood; United States National Institutes of Health; Ventricular; Viremia; Virus Diseases; World Health Organization; Zika Virus; base; calcification; congenital zika syndrome; experience; fetal; fetal brain injury; fetal medicine; gray matter; mouse model; myelination; nerve stem cell; neuroinflammation; neuropathology; nonhuman primate; pregnant; public health emergency; response; subcutaneous; subventricular zone; white matter; white matter damage

Zika virus (ZIKV) is transmitted to humans via the Aedes genus of mosquito. Following massive outbreaks of ZIKV infections in French Polynesia in 2013/14 and subsequently in Brazil in 2015, the World Health Organization (WHO) issued a Public Health Emergency of International Concern (Feb, 2016) based on the link between ZIKV and infants born with a spectrum of neurological insults including microcephaly and CNS lesions. Targeting of the fetal CNS is of major significance and concern due to the devastating outcome of microcephaly and the potential for sub-clinical yet significant impacts on the fetal CNS in the absence of microcephaly that could result in cognitive, behavioral and other CNS disorders. The olive baboon's (Papio anubis) similarity to humans in terms of genetics, brain development, placentation, size and immunology makes the baboon an excellent translational model for studies on ZIKV infection during pregnancy. Our research team has flavivirus experience, including ZIKV, in baboons. We complement this with expertise in neurobiology, maternal-fetal medicine and physiology necessary to accomplish our aims. The Oklahoma Baboon Research Resource provides us access to the needed numbers of timed-pregnant baboons to complete our aims. Our overarching hypothesis is that maternal ZIKV infection at different stages of gestation (first, second or third trimester) will result in different degrees of fetal CNS pathological phenotypes, the most severe arising from early gestation infection. Specific Aim 1- Analyze the fetal brain at 170dG (~term) to determine the effect of prolonged ZIKV infection performed at 50, 90 and 150dG (days gestation). Specific Aim 2: Analyze the fetal brain at 14 d post inoculation at early (50dG), mid (90dG) and late (150dG) gestation. We will also assess the maternal and fetal immune, inflammatory responses, viremia, fetal growth and placental pathology and function (umbilical blood flow) in response to ZIKV to relate timing of ZIKV infection and degree of inflammatory response to fetal outcome. The findings will provide essential data in a relevant non-human primate on the fetal outcome of ZIKV.

寨卡病毒（ZIKV）是一种常见的寨卡病毒。在2013/14年法属波利尼西亚和随后的2015年巴西大规模爆发ZIKV感染后，世界卫生组织（WHO）发布了国际关注的公共卫生紧急事件（2016年2月），基于ZIKV与出生时患有一系列神经损伤（包括小头畸形和CNS病变）的婴儿之间的联系。由于小头畸形的破坏性结局以及在不存在小头畸形的情况下对胎儿CNS的亚临床但显著影响的可能性（可能导致认知、行为和其他CNS疾病），因此靶向胎儿CNS具有重大意义和关注。橄榄狒狒（Papio anubis）在遗传学、大脑发育、胎盘形成、大小和免疫学方面与人类的相似性使得狒狒成为研究妊娠期间ZIKV感染的极好的转化模型。我们的研究团队在狒狒中有黄病毒的经验，包括ZIKV。我们在神经生物学、母胎医学和生理学方面的专业知识对此进行补充，以实现我们的目标。俄克拉荷马州狒狒研究资源为我们提供了所需数量的定时怀孕狒狒，以完成我们的目标。我们的总体假设是，在妊娠的不同阶段（妊娠早期、中期或晚期）的母体ZIKV感染将导致不同程度的胎儿CNS病理表型，最严重的是由妊娠早期感染引起的。具体目的1-分析170 dG（~足月）下的胎儿脑以确定在50、90和150 dG（妊娠天数）下进行的延长ZIKV感染的影响。具体目的2：分析孕早期（50 dG）、孕中期（90 dG）和孕晚期（150 dG）接种后14 d的胎脑。我们还将评估响应于ZIKV的母体和胎儿免疫、炎症反应、病毒血症、胎儿生长和胎盘病理学和功能（脐带血流量），以将ZIKV感染的时机和炎症反应的程度与胎儿结果相关联。这些发现将提供相关非人灵长类动物中关于ZIKV胎儿结局的基本数据。